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1. Compound ID: 1503
Structure type: polymer chemical repeating unit
; n=6-9
Compound class: CPS
Contained glycoepitopes: IEDB_114703,IEDB_146102,IEDB_146103,IEDB_149136,IEDB_591403,IEDB_910421
The structure is contained in the following publication(s):
- Article ID: 479
Fernández-Santana V, Cardoso F, Rodriguez A, Carmenate T, Peña L, Valdés Y, Hardy E, Mawas F, Heynngnezz L, Rodríguez MC, Figueroa I, Chang J, Toledo ME, Musacchio A, Hernández I, Izquierdo M, Cosme K, Roy R, Verez-Bencomo V "Antigenicity and immunogenicity of a synthetic oligosaccharide-protein conjugate vaccine against Haemophilus influenzae type b" -
Infection and Immunity 72(12) (2004) 7115-7123
Polysaccharide-protein conjugates as vaccines have proven to be very effective in preventing Haemophilus influenzae type b infections in industrialized countries. However, cost-effective technologies need to be developed for increasing the availability of anti-H. influenzae type b vaccines in countries from the developing world. Consequently, vaccine production with partially synthetic antigens is a desirable goal for many reasons. They may be rigidly controlled for purity and effectiveness while at the same time being cheap enough that they may be made universally available. We describe here the antigenicity and immunogenicity of several H. influenzae type b synthetic oligosaccharide-protein conjugates in laboratory animals. The serum of H. influenzae type b-immunized animals recognized our synthetic H. influenzae type b antigens to the same extent as the native bacterial capsular polysaccharide. Compared to the anti-H. influenzae type b vaccine employed, these synthetic versions induced similar antibody response patterns in terms of titer, specificity, and functional capacity. The further development of synthetic vaccines will meet urgent needs in the less prosperous parts of the world and remains our major goal.
Haemophilus, capsular polysaccharide, antibody response, vaccines, immunogenicity, conjugate vaccine, antigenicity, Haemophilus influenzae type b
NCBI PubMed ID: 15557635Journal NLM ID: 0246127Publisher: American Society for Microbiology
Correspondence: violeta@fq.uh.cu
Institutions: Center for the Study of Synthetic Antigens, Facultad de Quimica, Universidad de La Habana, Havana, Cuba 10400
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2. Compound ID: 1566
Structure type: polymer chemical repeating unit
Trivial name: HiB
Compound class: CPS
Contained glycoepitopes: IEDB_114703,IEDB_146102,IEDB_146103,IEDB_149136,IEDB_591403,IEDB_910421
The structure is contained in the following publication(s):
- Article ID: 487
Kuebler-Kielb J, Coxon B, Schneerson R "Chemical structure, conjugation, and cross-reactivity of Bacillus pumilus Sh18 cell wall polysaccharide" -
Journal of Bacteriology 186(20) (2004) 6891-6901
Bacillus pumilus strain Sh18 cell wall polysaccharide (CWP), cross-reactive with the capsular polysaccharide of Haemophilus influenzae type b, was purified and its chemical structure was elucidated using fast atom bombardment mass spectrometry, nuclear magnetic resonance techniques, and sugar-specific degradation procedures. Two major structures, 1,5-poly(ribitol phosphate) and 1,3-poly(glycerol phosphate), with the latter partially substituted by 2-acetamido-2-deoxy-α-galactopyranose (13%) and 2-acetamido-2-deoxy-α-glucopyranose (6%) on position O-2, were found. A minor component was established to be a polymer of →3-O-(2-acetamido-2-deoxy-β-glucopyranosyl)-1→4-ribitol-1-OPO3→. The ratios of the three components were 56, 34, and 10 mol%, respectively. The Sh18 CWP was covalently bound to carrier proteins, and the immunogenicity of the resulting conjugates was evaluated in mice. Two methods of conjugation were compared: (i) binding of 1-cyano-4-dimethylaminopyridinium tetrafluoroborate-activated hydroxyl groups of the CWP to adipic acid dihydrazide (ADH)-derivatized protein, and (ii) binding of the carbodiimide-activated terminal phosphate group of the CWP to ADH-derivatized protein. The conjugate-induced antibodies reacted in an enzyme-linked immunosorbent assay with the homologous polysaccharide and with a number of other bacterial polysaccharides containing ribitol and glycerol phosphates, including H. influenzae types a and b and strains of Staphylococcus aureus and Staphylococcus epidermidis.
Haemophilus influenzae, structure, capsular polysaccharide, polysaccharides, antibodies, spectrometry, cell wall, Staphylococcus, conjugate, Bacillus, cross-reactivity, Bacterial Vaccines
NCBI PubMed ID: 15466043Publication DOI: 10.1128/JB.186.20.6891-6901.2004Journal NLM ID: 2985120RPublisher: American Society for Microbiology
Correspondence: kielbj@mail.nih.gov
Institutions: Laboratory of Developmental and Molecular Immunity, NIH/NICHD,9000 Rockville Pike, Bldg. 6, Rm. 1A05, Bethesda, MD, USA
Methods: NMR-2D, FAB-MS, NMR, HF solvolysis, mild acid hydrolysis, Smith degradation
- Article ID: 1346
Abeygunawardana C, Williams TC, Sumner JS, Hennessey JP "Development and validation of an NMR-based identity assay for bacterial polysaccharides" -
Analytical Biochemistry 279(2) (2000) 226-240
A method utilizing NMR spectroscopy has been developed to confirm the identity of bacterial polysaccharides used to formulate a polyvalent pneumococcal polysaccharide vaccine. The method is based on 600 MHz proton NMR spectra of individual serotype-specific polysaccharides. A portion of the anomeric region of each spectrum (5.89 to 4.64 ppm) is compared to spectra generated for designated reference samples for each polysaccharide of interest. The selected region offers a spectral window that is unique to a given polysaccharide and is sensitive to any structural alteration of the repeating units. The similarity of any two spectral profiles is evaluated using a correlation coefficient (rho), where rho >/= 0.95 between a sample and reference profile indicates a positive identification of the sample polysaccharide. This method has been shown to be extremely selective in its ability to discriminate between serotype-specific polysaccharides, some of which differ by no more than a single glycosidic linkage. Furthermore, the method is rapid and does not require extensive sample manipulations or pretreatments. The method was validated as a qualitative identity assay and will be incorporated into routine quality control testing of polysaccharide powders to be used in preparation of the polyvalent pneumococcal vaccine PNEUMOVAX 23. The specificity and reproducibility of the NMR-based identity assay is superior to the currently used colorimetric assays and can be readily adapted for use with other bacterial polysaccharide preparations as well.
NMR, Bacterial, polysaccharide, polysaccharides, Bacterial polysaccharide, bacterial polysaccharides, assay, development, identity assay, method development, validation
NCBI PubMed ID: 10706792Publication DOI: 10.1006/abio.1999.447Journal NLM ID: 0370535Publisher: Academic Press
Correspondence: abey@merck.com
Institutions: Bioprocess and Bioanalytical Research, Merck Research Laboratories, West Point, Pensylvania, USA
Methods: NMR
- Article ID: 1406
Crane DT, Bolgiano B, Jones C "Comparison of the diphtheria mutant toxin, CRM197, with a Haemophilus influenzae type-b polysaccharide-CRM197 conjugate by optical spectroscopy" -
European Journal of Biochemistry 246 (1997) 320-327
Haemophilus, Haemophilus influenzae, capsular, mutant, spectroscopy, comparison, conjugate, Haemophilus influenzae type b, CRM197, diphtheria, optical spectroscopy, polysaccharases, toxin
Journal NLM ID: 0107600Publisher: Oxford, UK: Blackwell Science Ltd. on behalf of the Federation of European Biochemical Societies
Institutions: Laboratory for Molecular Structure, National Institute for Biological Standards and Control, South Mimms, UK
Methods: CD, fluorescence spectroscopy
- Article ID: 1428
Nilsson M, Norberg T "Solid-phase synthesis of an analog of Haemophilus influenzae type B capsular polysaccharide" -
Journal of Carbohydrate Chemistry 17(2) (1998) 305-316
A pentameric spacer-containing glyceryl-ribitol phosphate structure 2 was synthesized using a solid-phase protocol. The H-phosphonate 16, synthesized from a D-ribitol derivative and (S)-1,2-O-isopropylideneglycerol, was used as monomer. Compound 2 is a simplified fragment of Haemophilus influenzae capsular polysaccharide, where the glyceryl part replaces the original ribosyl moiety.
synthesis, polysaccharide, capsular polysaccharide, Haemophilus influenzae type b
Publication DOI: 10.1080/07328309808002330Journal NLM ID: 8218151Publisher: Marcel Dekker
Institutions: Department of Chemistry, Swedish University of Agricultural Sciences, P.O. Box 7015, S-750 07, Uppsala, Sweden
Methods: 13C NMR, 1H NMR, TLC, 31P NMR, chemical synthesis, chemical methods, MALDI-TOF MS, UV
- Article ID: 1519
Jones C "NMR assays for carbohydrate-based vaccines" -
Journal of Pharmaceutical and Biomedical Analysis 38(5) (2005) 840-850
Antibodies against the cell surface carbohydrates of many microbial pathogens protect against infection. This was initially exploited by the development of purified polysaccharide vaccines, but glycoconjugate vaccines, in which the cell surface carbohydrate of a microbial pathogen is covalently attached to an appropriate carrier protein, are proving the most effective means to generate this protective immunity. Carbohydrate-based vaccines against Haemophilus influenzae Type b, Neisseria meningitidis, Streptococcus pneumoniae and Salmonella enterica serotype Typhi (S. Typhi) are already licensed, and many similar products are in various stages of development. For many of these vaccines, biological assays are not available or are inappropriate and NMR spectroscopy is proving a valuable tool for the characterisation and quality control of existing and novel products. This review highlights some of the areas in which NMR spectroscopy is currently used, and where further developments may be expected.
capsular polysaccharide, O-acetylation, pneumonia, glycoconjugate, meningitis, carbohydrate-based vaccines, identity, typhoid
NCBI PubMed ID: 16087046Publication DOI: 10.1016/j.jpba.2005.01.044Journal NLM ID: 8309336Publisher: London: Elsevier
Institutions: Laboratory for Molecular Structure, National Institute for Biological Standards and Control, South Mimms, UK
Methods: NMR
- Article ID: 1660
Wieruszeski JM, Talaga P, Lippens G "Development of a high-resolution magic-angle spinning nuclear magnetic resonance identity assay of the capsular polysaccharide from Haemophilus influenzae type b present in cetavlon precipitate" -
Analytical Biochemistry 338(1) (2005) 20-25
We describe the use of high-resolution magic-angle spinning nuclear magnetic resonance to control the identity of the capsular polysaccharide from Haemophilus influenzae type b (Hib) present in the cetavlon precipitate. This step is one of the earliest in the purification of this polysaccharide, which is further used in the production of Hib polysaccharide-protein conjugate vaccine. The effects of sample procedure and magnetic field strength have been investigated. Since this assay is rapid and simple, it may represent a useful technique for characterization of polysaccharides present in complex and insoluble matrices. Moreover, it allows a rapid evaluation of the structure of the produced polysaccharides very early on during the production process and is as such an essential analytical tool before starting the purification process
Haemophilus, Haemophilus influenzae, structure, Bacterial, Non-U.S.Gov't, capsular, characterization, polysaccharide, analysis, capsular polysaccharide, polysaccharides, type, complex, evaluation, production, Magnetic Resonance Spectroscopy, nuclear, nuclear magnetic resonance, resonance, methods, vaccine, effect, conjugate, conjugate vaccine, purification, polysaccharide-protein conjugate, Haemophilus influenzae type b, assay, control, France, use, isolation & purification, high-resolution, magic angle, high resolution, precipitation, development, identity assay, polysaccharide-protein conjugate vaccine, Research Support, Cetrimonium Compounds, Haemophilus Vaccines, Hib, insoluble, matrices
NCBI PubMed ID: 15707931Journal NLM ID: 0370535Publisher: Academic Press
Institutions: CNRS/Universite de Lille 2, UMR 8525, Institut Pasteur de Lille, 1 rue du Professeur Calmette, 59019 Lille Cedex, France
Methods: NMR
- Article ID: 1673
Whitfield C, Valvano MA "Biosynthesis and expression of cell-surface polysaccharides in gram-negative bacteria" -
Advances in Microbial Physiology 35 (1993) 135-246
This chapter provides an overview of the molecular mechanisms involved in synthesis and expression of cell-surface polysaccharides in Gram-negative bacteria. Biosynthesis of many cell-surface components, including polysaccharides, involves enzymes and enzyme complexes found in the cytoplasmic membrane. The peptidoglycan layer is located immediately external to the cytoplasmic membrane and this layer is required for cell shape and rigidity. Gram-negative bacteria possess a periplasm that contains a variety of proteins and enzymes, including some involved in import and export of macromolecules. Biosynthesis of bacterial cell-surface polysaccharides involves a series of sequential processes: (1) biosynthesis of activated precursors in the cytoplasm, (2) formation of repeating units, (3) polymerization of repeating units, and (d) export of polysaccharides to the cell surface. The assembly of polysaccharide repeating units and subsequent polymerization reactions occur at the cytoplasmic membrane, using precursors synthesized in the cytoplasm. Genes for biosynthesis of cell-surface polysaccharides are chromosomal and are arranged in clusters of one or more transcriptional units. The synthesis of lipopolysaccharide (LPS) may be subject to complex regulation, but on-off switching is not possible due to the essential structural requirement for the lipid A-core LPS molecule. Most bacteria use extracellular polysaccharides (EPSs) for protection, and many regulatory strategies are directed to modulating EPS synthesis in response to appropriate environmental cues. Application of genetic and biochemical approaches has facilitated detailed analysis of complex, multicomponent systems, such as those involved in synthesis of cell-surface polysaccharides.
NCBI PubMed ID: 8310880Publication DOI: 10.1016/S0065-2911(08)60099-5Journal NLM ID: 0117147Institutions: Department of Microbiology, University of Guelph, Ontario, Canada, Department of Microbiology, University of Guelph, Guelph, Ontario, Canada, Department of Microbiology and Immunology, University of Western Ontario, London, Ontario, Canada, N6A 5C1
- Article ID: 1699
Bunse R, Henz HP "Interaction of the capsular polysaccharide of Haemophilus influenzae type b with C1q" -
Behring Institute Mitteilungen 93 (1993) 148-164
The Gram-negative pleomorphic bacterium Haemophilus influenzae type b (Hib) is the most common cause of bacterial meningitis in children below the age of 2. Virtually all infants between 3 and 18 month of age lack anticapsular antibodies. This is typical for the response to a T-cell-independent antigen. 3-5% of this group harbour Hib in the nasopharynx, but the incidence of disease is 1000-fold less. This implicates other factors in host susceptibility in addition to the absence of such antibodies. Under physiological conditions the purified complement subcomponent C1q interacts with polyribosylribitolphosphate (PRP), the capsular polysaccharide of Hib. The complex formation of C1q, the most basic serum protein, with this polyanion was demonstrated by several methods: agarose gel electrophoresis followed by immunoprecipitation in the gel and Coomassie staining; western blot analysis of C1q-PRP complexes; complex formation in electrophoretic separation of PRP; retardation of electrophoretic mobility of PRP was checked by blotting of this polysaccharide. These results were confirmed by time- and dose-dependent alteration of antigenetic properties detected by C1q-Sandwich-ELISA after coincubation with PRP. Preincubation of serum treated Hib with C1q significantly enhanced the O2-metabolism of polymorphonuclear leucocytes in chemiluminescence assay. Infants of the susceptible age group develop antibodies to several Hib outer membrane proteins (OMP) and lipooligosaccharides (LOS) in response to infection. The complement activation by immune complexes might be inhibited by the formation of C1q-PRP complexes. Our results do not support the thesis that C1q can be activated by the interaction with PRP as shown before for other polyanions. Differing C1q to PRP ratios could be a possible explanation for different host susceptibilities.
NCBI PubMed ID: 8172562Journal NLM ID: 0367532Publisher: Marburg/Lahn: Behringwerke AG
Institutions: Institute for Medical Microbiology and Virology, Heinrich-Heine-University, Düsseldorf, Germany
- Article ID: 2718
Bunse R, Heinz HP "Characterization of a monoclonal antibody to the capsule of Haemophilus influenzae type b, generated by in vitro immunization" -
Journal of Immunological Methods 177 (1994) 89-99
- Article ID: 2720
Granoff DM, Holmes SJ, Osterholm MT, McHugh JE, Lucas AH, Anderson EL, Belshe RB, Jacobs JL, Medley F, Murphy TV "Induction of immunologic memory in infants primed with Haemophilus influenzae type b conjugate vaccines" -
Journal of Infectious Diseases 168 (1993) 663-671
The ability of different Haemophilus influenzae type b conjugate vaccines to induce immunologic memory was compared in 381 infants who were vaccinated with one of three conjugate vaccines beginning at 2 months of age. All infants were vaccinated with unconjugated type b capsular polysaccharide, polyribosylribitol phosphate (PRP), at 12 months. In each group, high antibody responses were detected by 6-9 days after vaccination. One month after receiving PRP, infants primed with PRP conjugated to the outer membrane protein of Neisseria meningitidis or PRP oligomers conjugated to the cross-reactive mutant diphtheria protein, CRM197, had twofold higher total anti-PRP antibody concentrations than did infants primed with PRP conjugated to tetanus toxoid (P < .005). After the conjugate and the PRP boost, notable differences were present among vaccine groups with respect to the magnitude of the IgG anti-PRP antibody concentrations and light chain variable region usage as determined by idiotypic analysis. Thus, each of the conjugate vaccines primed infants for the ability to evoke memory antibody responses to PRP, but qualitative and quantitative differences in priming induced by different vaccines may affect their ability to confer protection against disease.
NCBI PubMed ID: 8354908Journal NLM ID: 0413675Publisher: Oxford: Oxford University Press
Institutions: Edward Mallinckrodt Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110
- Article ID: 2722
Hennessey JP, Bednar B, Manam V "Molecular size analysis of Haemophilus influenzae type B capsular polysaccharide" -
Journal of Liquid Chromatography 16 (1993) 1715-1729
Journal NLM ID: 7806595Publisher: Dekker
Methods: HPSEC, HPSEC-MALLS/RI, HPSEC-SV/RI
- Article ID: 2830
Siber GR, Anderson R, Habafy M, Gupta RK "Development of a guinea pig model to assess immunogenicity of Haemophilus influenzae type b capsular polysaccharide conjugate vaccines" -
Vaccine 13 (1995) 525-531
Journal NLM ID: 8406899Publisher: Elsevier
- Article ID: 4430
Ovodov YS "Bacterial capsular antigens. Structural patterns of capsular antigens" -
Biochemistry (Moscow) 71(9) (2006) 937-954
Structural patterns of bacterial capsular antigens including capsular polysaccharides and exoglycans are given in this review. In addition, the immunological activity of capsular antigens and their role in type specificity of bacteria are discussed.
structure, capsular polysaccharides, bacterial capsular antigens, bacterial exoglycans, immunological activity, type specificity
NCBI PubMed ID: 17009947Publication DOI: 10.1134/S000629790609001XJournal NLM ID: 0376536Publisher: Nauka/Interperiodica
Correspondence: ovoys@physiol.komisc.ru
Institutions: Institute of Physiology, Komi Science Center, Urals Branch of the Russian Academy of Sciences, Syktyvkar 167982, Russia
- Article ID: 4639
Willis LM, Whitfield C "Structure, biosynthesis, and function of bacterial capsular polysaccharides synthesized by ABC transporter-dependent pathways" -
Carbohydrate Research 378 (2013) 35-44
Bacterial capsules are formed primarily from long-chain polysaccharides with repeat-unit structures. A given bacterial species can produce a range of capsular polysaccharides (CPSs) with different structures and these help distinguish isolates by serotyping, as is the case with Escherichia coli K antigens. Capsules are important virulence factors for many pathogens and this review focuses on CPSs synthesized via ATP-binding cassette (ABC) transporter-dependent processes in Gram-negative bacteria. Bacteria utilizing this pathway are often associated with urinary tract infections, septicemia, and meningitis, and E. coli and Neisseria meningitidis provide well-studied examples. CPSs from ABC transporter-dependent pathways are synthesized at the cytoplasmic face of the inner membrane through the concerted action of glycosyltransferases before being exported across the inner membrane and translocated to the cell surface. A hallmark of these CPSs is a conserved reducing terminal glycolipid composed of phosphatidylglycerol and a poly-3-deoxy-d-manno-oct-2-ulosonic acid (Kdo) linker. Recent discovery of the structure of this conserved lipid terminus provides new insights into the early steps in CPS biosynthesis.
biosynthesis, capsular polysaccharides, glycosyltransferases, gram negative bacteria, export, ABC transporters
NCBI PubMed ID: 23746650Publication DOI: 10.1016/j.carres.2013.05.007Journal NLM ID: 0043535Publisher: Elsevier
Correspondence: C. Whitfield
Institutions: Department of Molecular and Cellular Biology, University of Guelph, Guelph, Ontario, Canada N1G 2W1
- Article ID: 4656
Laferriere C, Ravenscroft N, Wilson S, Combrink J, Gordon L, Petre J "Experimental design to optimize an Haemophilus influenzae type b conjugate vaccine made with hydrazide-derivatized tetanus toxoid" -
Glycoconjugate Journal 28(7) (2011) 463-472
The introduction of type b Haemophilus influenzae conjugate vaccines into routine vaccination schedules has significantly reduced the burden of this disease; however, widespread use in developing countries is constrained by vaccine costs, and there is a need for a simple and high-yielding manufacturing process. The vaccine is composed of purified capsular polysaccharide conjugated to an immunogenic carrier protein. To improve the yield and rate of the reductive amination conjugation reaction used to make this vaccine, some of the carboxyl groups of the carrier protein, tetanus toxoid, were modified to hydrazides, which are more reactive than the epsilon -amine of lysine. Other reaction parameters, including the ratio of the reactants, the size of the polysaccharide, the temperature and the salt concentration, were also investigated. Experimental design was used to minimize the number of experiments required to optimize all these parameters to obtain conjugate in high yield with target characteristics. It was found that increasing the reactant ratio and decreasing the size of the polysaccharide increased the polysaccharide:protein mass ratio in the product. Temperature and salt concentration did not improve this ratio. These results are consistent with a diffusion controlled rate limiting step in the conjugation reaction. Excessive modification of tetanus toxoid with hydrazide was correlated with reduced yield and lower free polysaccharide. This was attributed to a greater tendency for precipitation, possibly due to changes in the isoelectric point. Experimental design and multiple regression helped identify key parameters to control and thereby optimize this conjugation reaction.
conjugate vaccine, tetanus toxoid, Haemophilus influenzae type b, experimental design, Hib, Hydrazide, Diffusion controlled reaction
NCBI PubMed ID: 21850577Publication DOI: 10.1007/s10719-011-9344-3Journal NLM ID: 8603310Publisher: Kluwer Academic Publishers
Correspondence: craiglaferriere@gmail.com
Institutions: Canvax, 3561 Gallager Dr., Mississauga, ON, L5C 2N2, Canada
Methods: conjugation
- Article ID: 4835
Berti F, Ravenscroft N "Characterization of Carbohydrate Vaccines by NMR Spectroscopy" -
Methods in Molecular Biology 1331 (2015) 189-209
Physicochemical techniques are a powerful tool for the structural characterization of carbohydrate-based vaccines. High-field Nuclear Magnetic Resonance (NMR) spectroscopy has been established as an extremely useful and robust method for tracking the industrial manufacturing process of these vaccines from polysaccharide bulk antigen through to the final formulation. Here, we describe the use of proton NMR for structural identity and conformity testing of carbohydrate-based vaccines.
carbohydrates, capsular polysaccharide, antigens, nuclear magnetic resonance spectroscopy, vaccines
NCBI PubMed ID: 26169742Publication DOI: 10.1007/978-1-4939-2874-3_12Journal NLM ID: 9214969Publisher: Springer
Correspondence: francesco.x.berti@gsk.com
Institutions: Research, GSK Vaccines, Via Fiorentina 1, 53100, Siena, Italy
- Article ID: 5473
Zou W, Li J, Vinogradov E, Cox A "Removal of cell wall polysaccharide in pneumococcal capsular polysaccharides by selective degradation via deamination" -
Carbohydrate Polymers 218 (2019) 199-207
Pneumococcal cell wall polysaccharide (C-PS), a contaminant in pneumococcal capsular polysaccharide (Pn-PS) vaccines is degraded by mild deamination of the 4-amino-2-acetamido-2,4,6-tri-deoxy-galactose (AAT) in C-PS, which was carried out by addition of 5% aqueous sodium nitrite to a solution of polysaccharide in 5% aqueous acetic acid. Glycosidic linkage and functional groups such as O-acetates, phosphodiesters, and pyruvates were preserved under the conditions. The small fragments from degraded C-PS were removed by ultrafiltration or dialysis to provide essentially C-PS free Pn-PS. Because of the presence of AAT in its structure the deamination is not suitable for the purification of type 1 Pn-PS. Meanwhile, the mass and NMR spectroscopic analysis on the deamination products suggests that both type 1 Pn-PS and C-PS degraded following a major pathway of 5,4-hydride shift, cleavage of AAT O5-C1 bond, C1 hemiacetal formation, and its hydrolysis to release neighboring GalA- in type 1 Pn-PS and GalNAc(6-O-PCho)- in C-PS
mechanism, degradation, deamination, cell wall polysaccharide, pneumococcal capsular polysaccharide
NCBI PubMed ID: 31221321Publication DOI: 10.1016/j.carbpol.2019.03.070Journal NLM ID: 8307156Publisher: Elsevier
Correspondence: W. Zou
Institutions: Human Health Therapeutic Research Center, National Research Council of Canada, 100 Sussex Drive, Ottawa, Ontario, K1A 0R6, Canada
Methods: gel filtration, 13C NMR, 1H NMR, sugar analysis, MS/MS, MS, dialysis, SEC-HPLC, ultrafiltration, mild deamination
- Article ID: 6032
Berti F "NMR characterization of a multi-valent conjugate vaccine against Neisseria meningitidis A, C, W, Y and Haemophilus influenzae b infections" -
Journal of Pharmaceutical and Biomedical Analysis 205 (2021) 114302
Physicochemical technologies are a powerful tool for the structural characterization of vaccine antigens both at bulk level as well as on the final formulation. High-field Nuclear Magnetic Resonance (NMR) spectroscopy has been found to be an extremely and robust tool for tracking the industrial process manufacturing of carbohydrate-based vaccines. I have applied NMR spectroscopy to the characterization of a penta-valent conjugate vaccine against Neisseria meninigitidis group A, C, W, Y (MenACWY) and Haemophilus influenzae type b (Hib) infections, constituted of capsule derived polysaccharide fragments independently conjugated to CRM197 protein carrier (CRM-MenA, CRM-MenC, CRM-MenW, CRM-MenY, CRM-Hib). 1H NMR has been used for the identity testing of the carbohydrate antigens and of the vaccine formulation. The application of NMR-based assays on multivalent conjugate vaccines looks to be a promising approach for identity and stability analyses useful for future vaccines development.
glycoconjugates, nuclear magnetic resonance spectroscopy, vaccines, Haemophilus influenzae type b, Bacterial Infections, Neisseria meningitidis serogroup A/C/W/Y
NCBI PubMed ID: 34388671Publication DOI: 10.1016/j.jpba.2021.114302Journal NLM ID: 8309336Publisher: London: Elsevier
Correspondence: francesco.x.berti@gsk.com
Institutions: GSK, Via Fiorentina 1, 53100 Siena, Italy
Methods: 13C NMR, 1H NMR, 31P NMR, vaccine formulations
- Article ID: 6305
Richardson NI, Kuttel MM, St Michael F, Cairns C, Cox AD, Ravenscroft N "Cross-reactivity of Haemophilus influenzae type a and b polysaccharides: molecular modeling and conjugate immunogenicity studies" -
Glycoconjugate Journal 38(6) (2021) 735-746
Haemophilus influenzae is a leading cause of meningitis disease and mortality, particularly in young children. Since the introduction of a licensed conjugate vaccine (targeting the outer capsular polysaccharide) against the most prevalent serotype, Haemophilus influenzae serotype b, the epidemiology of the disease has changed and Haemophilus influenzae serotype a is on the rise, especially in Indigenous North American populations. Here we apply molecular modeling to explore the preferred conformations of the serotype a and b capsular polysaccharides as well as a modified hydrolysis resistant serotype b polysaccharide. Although both serotype b and the modified serotype b have similar random coil behavior, our simulations reveal some differences in the polysaccharide conformations and surfaces which may impact antibody cross-reactivity between these two antigens. Importantly, we find significant conformational differences between the serotype a and b polysaccharides, indicating a potential lack of cross-reactivity that is corroborated by immunological data showing little recognition or killing between heterologous serotypes. These findings support the current development of a serotype a conjugate vaccine.
conformation, capsular polysaccharide, molecular modeling, immunogenicity, cross protection, Haemophilus influenzae type a
NCBI PubMed ID: 34491462Publication DOI: 10.1007/s10719-021-10020-0Journal NLM ID: 8603310Publisher: Kluwer Academic Publishers
Correspondence: N. Ravenscroft
Institutions: Department of Chemistry, University of Cape Town, Rondebosch, 7701, South Africa, Department of Computer Science, University of Cape Town, Rondebosch, 7701, South Africa, Vaccine and Emerging Infections Research, Human Health Therapeutics Research Centre, National Research Council, Ottawa, ON, K1A 0R6, Canada
Methods: MD simulations, immunological assays, CarbBuilder, data analysis, convergence
- Article ID: 6318
Srtefanetti G, Maclennan CA, Micoli F "Impact and Control of Sugar Size in Glycoconjugate Vaccines" -
Molecules 27(19) (2022) 6432
Glycoconjugate vaccines have contributed enormously to reducing and controlling encapsulated bacterial infections for over thirty years. Glycoconjugate vaccines are based on a carbohydrate antigen that is covalently linked to a carrier protein; this is necessary to cause T cell responses for optimal immunogenicity, and to protect young children. Many interdependent parameters affect the immunogenicity of glycoconjugate vaccines, including the size of the saccharide antigen. Here, we examine and discuss the impact of glycan chain length on the efficacy of glycoconjugate vaccines and report the methods employed to size polysaccharide antigens, while highlighting the underlying reaction mechanisms. A better understanding of the impact of key parameters on the immunogenicity of glycoconjugates is critical to developing a new generation of highly effective vaccines.
glycoconjugates, vaccine, immunogenicity, fragmentation of polysaccharides, sugar length
NCBI PubMed ID: 36234967Publication DOI: 10.3390/molecules27196432Journal NLM ID: 100964009Publisher: Basel, Switzerland: MDPI
Correspondence: G. Srtefanetti
Institutions: Department of Biomolecular Sciences, University of Urbino Carlo Bo, 61029 Urbino, Italy, Enteric and Diarrheal Diseases, Global Health, Bill & Melinda Gates Foundation, 500 5th Ave. N, Seattle, WA 98109, USA, The Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7DQ, UK, The Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, UK, GSK Vaccines Institute for Global Health, 53100 Siena, Italy
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3. Compound ID: 2327
Structure type: polymer chemical repeating unit
; 10000
Compound class: CPS
Contained glycoepitopes: IEDB_114703,IEDB_146102,IEDB_146103,IEDB_149136,IEDB_591403,IEDB_910421
The structure is contained in the following publication(s):
- Article ID: 794
D'Ambra A, Baugher JE, Concannon PE, Pon RA, Michon F "Direct and indirect methods for molar-mass analysis of fragments of the capsular polysaccharide of Haemophilus influenzae type b" -
Analytical Biochemistry 250(2) (1997) 228-236
Two methods are described for direct molar-mass measurement of low-molar-mass fragments obtained by oxidative cleavage of the capsular polysaccharide of Haemophilus influenzae type b. Absolute molar masses were determined by size-exclusion chromatography (SEC) with detection by multiangle laser-light-scattering photometry (MALLS) and differential refractometry (RI). The end-group structure of the polysaccharide fragments allowed the direct measurement of average chain length by quantitative 1H NMR, from which molar masses were derived. Variation between the molar masses obtained by the two methods ranged from 5 to 7%. When molar masses estimated by indirect methods were compared to SEC-MALLS/RI data, significant deviations were observed. Analysis by SEC with secondary calibration with dextran standards gave molar masses that exceeded the SEC-MALLS/RI data by as much as 2.5-fold. Molar masses estimated by a combination of colorimetric assays varied from the SEC-MALLS/RI data by as much as 50%. These results demonstrated the applicability and superior accuracy of the direct methods of molar-mass determination of the polysaccharide fragments.
NMR, Haemophilus, Haemophilus influenzae, structure, chemistry, variation, capsular, polysaccharide, analysis, capsular polysaccharide, chain, type, Magnetic Resonance Spectroscopy, method, fragment, methods, chromatography, measurement, quantitative, Bacterial Capsules, Haemophilus influenzae type b, detection, 1H NMR, chain length, cleavage, colorimetry, oxidative
NCBI PubMed ID: 9245443Journal NLM ID: 0370535Publisher: Academic Press
Institutions: Research Department, North American Vaccine, Inc., Beltsville, Maryland 20705
Methods: NMR, MS, colorimetry, oxidative partial depolymerization
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4. Compound ID: 8201
|
Subst-(1--P--3)--{{{-b-D-Ribf-(1-1)-D-Rib-ol-(5--P--3)--}}}/n=5-8/-b-D-Ribf-(1-1)-D-Rib-ol
Subst = OHCH2CH2OCH2CHNH2 = SMILES NCCOCC{1}O |
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Structure type: oligomer
Trivial name: synthetic hexasaccharide of the CPS
Contained glycoepitopes: IEDB_114703,IEDB_146102,IEDB_146103,IEDB_149136,IEDB_591403,IEDB_910421
The structure is contained in the following publication(s):
- Article ID: 3594
Pozsgay V "Recent developments in synthetic oligosaccharide-based bacterial vaccines" -
Current Topics in Medicinal Chemistry 8(2) (2008) 126-140
Synthetic advances made possible chemical assembly of complex oligosaccharide fragments of polysaccharide domains on the surface of human pathogenic bacteria. These oligosaccharides may be recognized by antibodies raised against high molecular weight, native, polysaccharides. In addition to their antigenicity, synthetic oligosaccharides can also function as haptens in their protein conjugates that can elicit not only oligo- but also polysaccharide-specific IgG antibodies in animal models and in humans. A major milestone in the development of new generation vaccines was the demonstration that protein conjugates of synthetic fragments of the capsular polysaccharide of Haemophilus influenzae type b are as efficacious in preventing childhood meningitis and other diseases as is the corresponding licensed commercial vaccine containing the bacterial polysaccharide. The lessons learnt in this and other endeavors described herein are manifold. For example, they teach us about the significance of the oligosaccharide epitope size, the number of their copies per protein in the conjugate, the possible effect of the spacer on anti-saccharide immune response, and the proper choice of the carrier protein combined with the selection of the animal model. The H. influenzae b story also teaches us that that the synthetic approach can be commercially viable.
Haemophilus influenzae, Streptococcus pneumoniae, Oligosaccharides, Shigella dysenteriae type 1, keyhole limpet hemocyanin, keyhole limpet hemocyanine
NCBI PubMed ID: 18289082Journal NLM ID: 101119673Publisher: Bentham Science Publishers
Correspondence: pozsgayv@mail.nih.gov
Institutions: National Institute of Child Health and Human Development, National Institutes of Health, 6 Center Dr., MSC 2423, Bethesda, MD 20892-2423, USA
Methods: chemical synthesis
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5. Compound ID: 8353
Structure type: polymer chemical repeating unit
Contained glycoepitopes: IEDB_114703,IEDB_136906,IEDB_137472,IEDB_141794,IEDB_146102,IEDB_146103,IEDB_149136,IEDB_151528,IEDB_190606,IEDB_591403,IEDB_910421,SB_7
The structure is contained in the following publication(s):
- Article ID: 3631
Shashkov AS, Malysheva VA, Naumova IB, Streshinskaya GM, Evtushenko LI "Poly(ribofuranosylribitol phosphate) in cell wall of Agromyces cerinus subsp. nitratus VKM Ac-1351" -
Bioorganicheskaya Khimia = Bioorganic Chemistry [Russian] 19(4) (1993) 433-438
Cell wall of Agromyces cerinus subsp. nitratus contains ribitolteichoic acids, previously unknown in prokaryotic cells. The following structure of the repeating unit of the chain was proposed: [see formula]. The structure of the polymer was elucidated by NMR spectroscopy and confirmed by chemical analysis.
structure, cell, phosphate, cell wall, ribitol, teichoic acid, Agromyces, Agromyces cerinus
Journal NLM ID: 7804941WWW link: http://www.rjbc.ru/arc/19/4/0433-0438.pdfPublisher: Moskva: Nauka
Institutions: N.D. Zelinsky Institute of Organic Chemistry, Academy of Sciences, Moscow, Russia.
Methods: 13C NMR, 1H NMR, NMR-2D, chemical analysis, 31P NMR
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6. Compound ID: 10989
Structure type: polymer chemical repeating unit
Compound class: teichoic acid
Contained glycoepitopes: IEDB_114703,IEDB_136906,IEDB_137472,IEDB_141794,IEDB_146102,IEDB_146103,IEDB_149136,IEDB_151528,IEDB_190606,IEDB_591403,IEDB_910421,SB_7
The structure is contained in the following publication(s):
- Article ID: 4450
Naumova IB, Shashkov AS "Anionic polymers in cell walls of Gram-positive bacteria" -
Biochemistry (Moscow) 62(8) (1997) 809-840
Information on the prevalence, compositions, and structures of anionic carbohydrate-containing polymers of cell walls of Gram-positive bacteria is summarized. The data suggest that these polymers are important for normal functioning of bacterial cells and require further studies. Structural data on teichoic acids found in the literature published over the last few years are discussed. This is a very diverse class of polymers whose structure-specific pathways of degradation were studied and NMR spectra were examined. Unique comprehensive tables of 13C-NMR spectroscopic data (mainly obtained by the authors) on these polymers are given in the Appendix. Other tables summarize data on teichuronic acids, sugar-phosphate polymers, acid polysaccharides, and structural variants of bonds between acid polysaccharides and peptidoglycans known from the literature. Functions of anionic polymers and their possible chemotaxonomic applications are discussed
13C-NMR, NMR, structure, cell wall, composition, teichoic acid, teichuronic acid, Gram-positive, gram-positive bacteria, taxonomy
NCBI PubMed ID: 9360295Journal NLM ID: 0376536Publisher: Nauka/Interperiodica
Institutions: School of Biology, Lomonosov Moscow State University, Russia
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7. Compound ID: 14027
Structure type: polymer chemical repeating unit
Aglycon: carrier protein CRM197,OMPC
Compound class: CPS
Contained glycoepitopes: IEDB_114703,IEDB_146102,IEDB_146103,IEDB_149136,IEDB_591403,IEDB_910421
The structure is contained in the following publication(s):
- Article ID: 5541
Sun X, Stefanetti G, Berti F, Kasper DL "Polysaccharide structure dictates mechanism of adaptive immune response to glycoconjugate vaccines" -
Proceedings of the National Academy of Sciences of the USA 116(1) (2019) 193-198
Glycoconjugate vaccines are among the most effective interventions for preventing several serious infectious diseases. Covalent linkage of the bacterial capsular polysaccharide to a carrier protein provides CD4+ T cells with epitopes that facilitate a memory response to the polysaccharide. Classically, the mechanism responsible for antigen processing was thought to be similar to what was known for hapten-carrier conjugates: protease digestion of the carrier protein in the endosome and presentation of a resulting peptide to the T cell receptor on classical peptide-recognizing CD4+ T cells. Recently, an alternative mechanism has been shown to be responsible for the memory response to some glycoconjugates. Processing of both the protein and the polysaccharide creates glycopeptides in the endosome of antigen-presenting cells. For presentation, the peptide portion of the glycopeptide is bound to MHCII, allowing the covalently linked glycan to activate carbohydrate-specific helper CD4+ T cells (Tcarbs). Herein, we assessed whether this same mechanism applies to conjugates prepared from other capsular polysaccharides. All of the glycoconjugates tested induced Tcarb-dependent responses except that made with group C Neisseria meningitidis; in the latter case, only peptides generated from the carrier protein were critical for helper T cell recognition. Digestion of this acid-sensitive polysaccharide, a linear homopolymer of α(2 → 9)-linked sialic acid, to the size of the monomeric unit resulted in a dominant CD4+ T cell response to peptides in the context of MHCII. Our results show that different mechanisms of presentation, based on the structure of the carbohydrate, are operative in response to different glycoconjugate vaccines.
vaccine, glycoconjugate, Tcarb, antigen presentation, group C Neisseria meningitidis
NCBI PubMed ID: 30510007Publication DOI: 10.1073/pnas.1816401115Journal NLM ID: 7505876Publisher: National Academy of Sciences
Correspondence: D.L. Kasper
Institutions: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, Graduate Program in Immunology, Harvard Medical School, Boston, MA 02115, Department of Chemistry, University of Milan, 20133 Milan, Italy, Technical R&D, GSK Vaccines, 53100 Siena, Italy
Methods: ELISA, biological assays, serological methods, HPSEC, statistical analysis, immunization, conjugation, flow cytometry analysis, antigen presentation by BMDCs
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8. Compound ID: 14766
|
{{{-b-D-Ribf-(1-1)-D-Rib-ol-(5--P--3)--}}}/n=3-9/-b-D-Ribf-(1-1)-D-Rib-ol-(5---P---/(->1)(CH2)5NH2/ |
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Structure type: oligomer
; n=3,5,7,9
Aglycon: (->1)(CH2)5NH2
Compound class: CPS
Contained glycoepitopes: IEDB_114703,IEDB_146102,IEDB_146103,IEDB_149136,IEDB_591403,IEDB_910421
The structure is contained in the following publication(s):
- Article ID: 5806
Li R, Yu H, Chen X "Recent progress in chemical synthesis of bacterial surface glycans" -
Current Opinion in Chemical Biology 58 (2020) 121-136
With the continuing advancement of carbohydrate chemical synthesis, bacterial glycomes have become increasingly attractive and accessible synthetic targets. Although bacteria also produce carbohydrate-containing secondary metabolites, our review here will cover recent chemical synthetic efforts on bacterial surface glycans. The obtained compounds are excellent candidates for the development of improved structurally defined glycoconjugate vaccines to combat bacterial infections. They are also important probes for investigating glycan–protein interactions. Glycosylation strategies applied for the formation of some challenging glycosidic bonds of various uncommon sugars in a number of recently synthesized bacterial surface glycans are highlighted.
synthesis, carbohydrate, glycosyltransferase, glycoconjugate vaccine, Bacterial glycan
NCBI PubMed ID: 32920523Publication DOI: 10.1016/j.cbpa.2020.08.003Journal NLM ID: 9811312Publisher: London: Elsevier
Correspondence: Chen Xi
Institutions: Department of Chemistry, University of California Davis, Davis, CA, USA
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9. Compound ID: 16264
Structure type: polymer chemical repeating unit
; 200000
Compound class: CPS
Contained glycoepitopes: IEDB_114703,IEDB_146102,IEDB_146103,IEDB_149136,IEDB_591403,IEDB_910421
The structure is contained in the following publication(s):
- Article ID: 6302
Qin CJ, Hu J, Tong W, Zhang TT, Tian GZ, Zou XP, Liu JK, Yin J "Determination of ribose and phosphorus contents in Haemophilus influenzae type b capsular polysaccharide by a quantitative NMR method using a single internal standard" -
Chinese Journal of Natural Medicines = Zhongguo Tianran Yaowu 20(8) (2022) 633-640
The ribose and phosphorus contents in Haemophilus influenzae type b (Hib) capsular polysaccharide (CPS) are two important chemical indexes for the development and quality control of Hib conjugate vaccine. A quantitative 1H- and 31P-NMR method using a single internal standard was developed for simultaneous determination of ribose and phosphorus contents in Hib CPS. Hexamethylphosphoramide (HMPA) was successfully utilized as an internal standard in quantitative 1H-NMR method for ribose content determination. The ribose and phosphorus contents were found to be affected by the concentration of polysaccharide solution. Thus, 15-20 mg·L-1 was the optimal concentration range of Hib CPS in D2O solution for determination of ribose and phosphorus contents by this method. The ribose and phosphorus contents obtained by the quantitative NMR were consistent with those obtained by traditional chemical methods. In conclusion, this quantitative 1H- and 31P-NMR method using a single internal standard shows good specificity, accuracy and precision, providing a valuable approach for the quality control of Hib glycoconjugate vaccines.
capsular polysaccharide, Haemophilus influenzae type b, phosphorus content, quantitative (1)H-NMR, quantitative (31)P-NMR, ribose content
NCBI PubMed ID: 36031235Publication DOI: 10.1016/S1875-5364(22)60184-5Journal NLM ID: 101504416Publisher: Beijing: Science Press; Elsevier
Correspondence: J.K. Liu
; J. Yin
Institutions: Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Wuxi, China, National & Local Joint Engineering Laboratory for Novel Vaccine Development Technology, Beijing Minhai Biotechnology Co., Ltd., Beijing, China, Jiangnan University-Beijing Minhai Biotechnology Joint Research Center of Carbohydrate-Based Vaccines, Jiangnan University, Wuxi, China
Methods: guantitative NMR method, quantitative 1H NMR, quantitative 31P NMR
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10. Compound ID: 16268
Structure type: polymer chemical repeating unit
Compound class: CPS
Contained glycoepitopes: IEDB_114703,IEDB_146102,IEDB_146103,IEDB_149136,IEDB_591403,IEDB_910421
The structure is contained in the following publication(s):
- Article ID: 6305
Richardson NI, Kuttel MM, St Michael F, Cairns C, Cox AD, Ravenscroft N "Cross-reactivity of Haemophilus influenzae type a and b polysaccharides: molecular modeling and conjugate immunogenicity studies" -
Glycoconjugate Journal 38(6) (2021) 735-746
Haemophilus influenzae is a leading cause of meningitis disease and mortality, particularly in young children. Since the introduction of a licensed conjugate vaccine (targeting the outer capsular polysaccharide) against the most prevalent serotype, Haemophilus influenzae serotype b, the epidemiology of the disease has changed and Haemophilus influenzae serotype a is on the rise, especially in Indigenous North American populations. Here we apply molecular modeling to explore the preferred conformations of the serotype a and b capsular polysaccharides as well as a modified hydrolysis resistant serotype b polysaccharide. Although both serotype b and the modified serotype b have similar random coil behavior, our simulations reveal some differences in the polysaccharide conformations and surfaces which may impact antibody cross-reactivity between these two antigens. Importantly, we find significant conformational differences between the serotype a and b polysaccharides, indicating a potential lack of cross-reactivity that is corroborated by immunological data showing little recognition or killing between heterologous serotypes. These findings support the current development of a serotype a conjugate vaccine.
conformation, capsular polysaccharide, molecular modeling, immunogenicity, cross protection, Haemophilus influenzae type a
NCBI PubMed ID: 34491462Publication DOI: 10.1007/s10719-021-10020-0Journal NLM ID: 8603310Publisher: Kluwer Academic Publishers
Correspondence: N. Ravenscroft
Institutions: Department of Chemistry, University of Cape Town, Rondebosch, 7701, South Africa, Department of Computer Science, University of Cape Town, Rondebosch, 7701, South Africa, Vaccine and Emerging Infections Research, Human Health Therapeutics Research Centre, National Research Council, Ottawa, ON, K1A 0R6, Canada
Methods: MD simulations, immunological assays, CarbBuilder, data analysis, convergence
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